Phosphoramidon, an inhibitor of endothelin-converting enzyme, prevents indomethacin-induced gastric mucosal damage in rats.
Endothelin-1 (ET-1) is produced from inactive precursor big ET-1 by endothelin-converting enzyme-1 (ECE-1), a membrane-bound metalloprotease, structurally similar to another metalloprotease, neutral endopeptidase 24.11 (NEP). Although both phosphoramidon and thiorphan are metalloprotease inhibitors, the ECE activity is inhibited by phosphoramidon but not by thiorphan, a specific inhibitor of NEP. Therefore, to investigate whether an ECE inhibitor can prevent indomethacin-induced gastric mucosal damage in rats, we compared the effects between the two metalloprotease inhibitors on both gastric mucosal integrity and the levels of ET-1 and big ET-1 in gastric tissue. Phosphoramidon significantly decreased ET-1 levels, causing a concomitant big ET-1 increase and dose-dependently attenuated indomethacin-induced gastric mucosal damage. By contrast, thiorphan neither changed the ratio of ET-1/big ET-1 nor attenuated the damage. In conclusion, the prevention of gastric mucosal damage by an ECE inhibitor indicates that endogenous ET-1 may play an important role in the pathogenesis of indomethacin-induced gastric mucosal damage.
Matsumaru
K
K
Department of Internal Medicine, University of Tsukuba, Ibaraki, Japan.
Kashimura
H
H
Hassan
M
M
Nakahara
A
A
Goto
K
K
Fukutomi
H
H
Muto
H
H
Tanaka
N
N
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D019332:Endothelin-1 / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006020:Glycopeptides / Q000627:therapeutic use*; D007213:Indomethacin / Q000633:toxicity*; D008297:Male; D008666:Metalloendopeptidases; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013272:Stomach Diseases / Q000139:chemically induced / Q000517:prevention & control*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon; D007213:Indomethacin